Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN

Bjorklund, Chad C.; Kang, Jian; Amatangelo, Michael; Polonskaia, Ann; Katz, Mark H.; Chiu, Hsiling; Couto, Suzana; Wang, Maria; Ren, Yan; Ortiz, María; Towfic, Fadi; Flynt, J Erin; Pierceall, William E.; Thakurta, Anjan

doi:10.1038/s41375-019-0620-8

Cited by 145 publications

(109 citation statements)

References 11 publications

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“…19,20 Dysregulation of c-Myc and IRF4 are commonly observed in MM cells, and experiments have shown that persistent degradation or downregulation of Ikaros and Aiolos with iberdomide results in downregulation of c-Myc and IRF4, which leads to inhibition of MM cell growth and apoptosis. 7,8 Profound B-lymphocyte reduction and the activation of T lymphocytes observed in the current study support the investigation in MM. A dose regimen using a high dose (1 mg instead of 0.3 mg) of iberdomide with drug holidays is recommended for MM to maximize the immunomodulatory effects and minimize neutropenia.…”

Section: Discussionsupporting

confidence: 85%

“…Degradation of Ikaros and Aiolos disrupts the c-Myc/IRF4 axis, which is implicated in the pathogenesis of MM. 7,8 In addition, polymorphisms in genes encoding Ikaros and Aiolos have been associated with the risk of developing SLE. 6 Here, we report the results of the first-in-human, single-ascending-dose (SAD) and multiple-ascendingdose (MAD) studies conducted in healthy subjects to characterize the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of iberdomide.…”

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confidence: 99%

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First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator

Gaudy

Schäfer

et al. 2020

Clinical Pharm in Drug Dev

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Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC-220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple-dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7-day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose-proportional manner. Terminal half-life was 9-13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (E max , 92.4%; EC 50 , 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (E max , 34.8%; EC 50 , 0.932 ng/mL). Lipopolysaccharide-stimulated proinflammatory cytokines (IL-1α, IL-1β) were reduced, but anti-CD3-stimulated IL-2 and interferon-γ were increased. Iberdomide 1 mg once daily partially decreased T-cellindependent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose-dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7-day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator

Gaudy

Schäfer

et al. 2020

Clinical Pharm in Drug Dev

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“…A third promising new strategy is the use of bispecific T-cell engager, such as AMG 701 85,86 . Cereblon E3 ligase modulators also appear promising 87 .…”

Section: Investigational Treatment Approachesmentioning

confidence: 99%

Multiple myeloma current treatment algorithms

2020

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The treatment of multiple myeloma (MM) continues to evolve rapidly with arrival of multiple new drugs, and emerging data from randomized trials to guide therapy. Along the disease course, the choice of specific therapy is affected by many variables including age, performance status, comorbidities, and eligibility for stem cell transplantation. In addition, another key variable that affects treatment strategy is risk stratification of patients into standard and high-risk MM. High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), gain 1q, del(17p), or p53 mutation. In this paper, we provide algorithms for the treatment of newly diagnosed and relapsed MM based on the best available evidence. We have relied on data from randomized controlled trials whenever possible, and when appropriate trials to guide therapy are not available, our recommendations reflect best practices based on non-randomized data, and expert opinion. Each algorithm has been designed to facilitate easy decision-making for practicing clinicians. In all patients, clinical trials should be considered first, prior to resorting to the standard of care algorithms we outline.

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“… 95 Preclinical and clinical studies have already confirmed the strong synergism of IMiD with PI and with mAb. 97-102 Recently, iberdomide, a higher affinity CRBN E3-ligase modulator (CELMoD), showed significant preclinical activity against IMiD-resistant MM cells, 103 and ongoing clinical trials are examining its efficacy in RRMM resistant to lenalidomide and pomalidomide. Promising results have also been recently reported with the more potent CELMoD CC-92480, currently under investigation to treat IMiD-resistant RRMM.…”

Section: Biologically-based Treatmentsmentioning

confidence: 99%

Multiple myeloma: the (r)evolution of current therapy and a glance into future

Gullà

Anderson

2020

haematol

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Over the past 20 years, the regulatory approval of several novel agents to treat multiple myeloma (MM) has prolonged median patient survival from 3 to 8-10 years. Increased understanding of MM biology has translated to advances in diagnosis, prognosis, and response assessment, as well as informed the development of targeted and immune agents. Here we provide an overview of the recent progress in MM, and highlight research areas of greatest promise to further improve patient outcome in the future.

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Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN

Cited by 145 publications

References 11 publications

First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator

First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator

Multiple myeloma current treatment algorithms

Multiple myeloma: the (r)evolution of current therapy and a glance into future

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